PUMA and BIM are required for oncogene inactivation-induced apoptosis.
PUMA and BIM are required for oncogene inactivation-induced apoptosis.
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DOI：
10.1126/scisignal.2003483
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发表时间：
2013-03-26
影响因子：
7.3
通讯作者：
Cheng EH
中科院分区：
文献类型：
--
作者：
Bean GR;Ganesan YT;Dong Y;Takeda S;Liu H;Chan PM;Huang Y;Chodosh LA;Zambetti GP;Hsieh JJ;Cheng EH
酪氨酸激酶抑制剂的临床疗效支持不同的癌症亚群依赖于特定的驱动突变生存，这种现象称为“癌基因成瘾”。我们证明，在乳腺癌与扩增的基因编码的人表皮生长因子受体2（HER 2）和肺癌与表皮生长因子受体（EGFR）突变体的酪氨酸激酶抑制剂的关键细胞凋亡效应。含有BH 3结构域的蛋白BIM和BH 3A可以直接激活促凋亡蛋白BAX和巴克以透化线粒体，导致半胱天冬酶激活和凋亡。我们描绘的信号转导途径，导致诱导BIM和酪氨酸激酶抑制剂的CD 4A。抑制促分裂原激活或细胞外信号调节蛋白激酶激酶（MEK）-细胞外信号调节激酶（ERK）途径导致BIM丰度增加，而拮抗磷酸肌醇3-激酶（PI 3 K）-AKT途径触发FOXO转录因子的核转位，直接激活BIA启动子。在小鼠乳腺肿瘤模型中，HER 2失活后，CD 4A和BIM的丰度增加。此外，Bim或Puma的缺乏损害了半胱天冬酶的活化，并减少了由HER 2失活引起的肿瘤消退。类似地，Puma的缺乏阻碍了EGFR激活突变体失活后EGFRL 858 R驱动的小鼠肺肿瘤的消退。总的来说，我们的研究确定了BIA和BIM作为互连激酶信号网络和依赖于细胞凋亡程序的哨兵，这为设计基于新细胞死亡机制的抗癌策略提供了治疗见解。
The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called “oncogene addiction.” We demonstrate that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis. We delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of the mitogen-activated or extracellular signal–regulated protein kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) pathway caused increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase (PI3K)–AKT pathway triggered nuclear translocation of the FOXO transcription factors, which directly activated the PUMA promoter. In a mouse breast tumor model, the abundance of PUMA and BIM was increased after inactivation of HER2. Moreover, deficiency of Bim or Puma impaired caspase activation and reduced tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma impeded the regression of EGFRL858R-driven mouse lung tumors upon inactivation of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism–based anticancer strategies.
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影响因子：
16
作者：
Dehan, Elinor;Bassermann, Florian;Guardavaccaro, Daniele;Vasiliver-Shamis, Gaia;Cohen, Michael;Lowes, Kym N.;Dustin, Michael;Huang, David C. S.;Taunton, Jack;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
8
作者：
Ni Chonghaile T;Letai A
通讯作者：
Letai A
吉非替尼诱导的表达突变体EGFR的NSCLC细胞系杀死需要BIM，并且可以通过BH3 Mimetics增强。
影响因子：
15.8
作者：
Cragg MS;Kuroda J;Puthalakath H;Huang DC;Strasser A
通讯作者：
Strasser A
BIM的诱导对于突变体EGFR依赖性肺腺癌中EGFR激酶抑制剂触发的凋亡至关重要。
影响因子：
15.8
作者：
Gong, Yixuan;Somwar, Romel;Politi, Katerina;Balak, Marissa;Chmielecki, Juliann;Jiang, Xuejun;Pao, William
通讯作者：
Pao, William
FOXO转录因子直接激活BIM基因表达并促进交感神经元中的凋亡。
影响因子：
7.8
作者：
Gilley, Jonathan;Coffer, Paul J;Ham, Jonathan
通讯作者：
Ham, Jonathan